Celastrol as an Exercise Mimetic to Modestly Slow Aging
Researchers continue to identify compounds that marginally affect aging in short-lived species. The Interventions Testing Program at the NIA continues to show that most of these have no effect on life span when rigorously assessed in mice. The few points of comparison we do have between mice and humans suggest that effects on life span in mice resulting from manipulation of metabolism become much smaller in humans. Long lived species do not have the same flexibility in metabolic determination of the pace of aging as exists in short lived species. This entire branch of longevity science, focused on exercise mimetics, calorie restriction mimetics, and other similar approaches, should not be expected to deliver meaningful results to human medicine in terms of years of life gained. Nonetheless, these efforts persist.
Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.
This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction. We analyzed age-stratified muscle transcriptome data from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. Subsequently, myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction.
Celastrol, a bioactive triterpenoid, was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6%, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.